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In June 2019, the Department of Veterans Affairs (VA) launched the VA Mission Act, which expanded veterans' health-care access to the private sector. Since civilian primary care providers may see more veterans in their practice, it will be important to understand the unique experiences, comorbidities, and culture of this population in order to provide optimal care. Military service members (SMs) are at an increased risk for traumatic brain injury (TBI), and comorbidities, such as post traumatic stress disorder (PTSD), increasing the likelihood of prolonged symptoms. Military training and repetitive low-level blast exposure may cause symptoms similar to TBI or increase long-term negative effects in SMs. Military culture often has a strong influence in this population. Those who serve in the military identify with military values and have a strong team mentality, which places emphasis on the mission above all else, not accepting defeat, and not ever leaving a fellow SM behind. These values can impact the way a SM/veteran seeks care and/or communicates with his or her health-care provider. Taking a detailed history to understand how these factors apply, as well as screening for mental health comorbidities, are recommended. Understanding the military cultural influences can assist in promoting a stronger therapeutic alliance and encourage more open communication. Ultimately, it is the trusting and respectful relationship between the SM/veteran and the provider that will determine the most effective treatment and result in the most effective resolution of TBI and comorbid symptoms.

Traumatic brain injury (TBI) is deemed the "signature injury" of recent military conflicts in Afghanistan and Iraq, largely because of increased blast exposure. Injuries to the brain can often be misdiagnosed, leading to further complications in the future. Therefore, the use of protein biomarkers for the screening and diagnosis of TBI is urgently needed. In the present study, we have investigated the plasma levels of soluble cellular prion protein (PrPC) as a novel biomarker for the diagnosis of primary blast-induced TBI (bTBI). We hypothesize that the primary blast wave can disrupt the brain and dislodge extracellular localized PrPC, leading to a rise in concentration within the systemic circulation. Adult male Sprague–Dawley rats were exposed to single pulse shockwave overpressures of varying intensities (15-30 psi or 103.4–206.8 kPa] using an advanced blast simulator. Blood plasma was collected 24 h after insult, and PrPC concentration was determined with a modified commercial enzyme-linked immunosorbent assay (ELISA) specific for PrPC. We provide the first report that mean PrPC concentration in primary blast exposed rats (3.97 ng/mL±0.13 SE) is significantly increased compared with controls (2.46 ng/mL±0.14 SE; two tailed test p<0.0001). Furthermore, we report a mild positive rank correlation between PrPC concentration and increasing blast intensity (psi) reflecting a plateaued response at higher pressure magnitudes, which may have implications for all military service members exposed to blast events. In conclusion, it appears that plasma levels of PrPC may be a novel biomarker for the detection of primary bTBI.

Blast waves generated by improvised explosive devices (IEDs) cause traumatic brain injury (TBI) in soldiers and civilians. In vivo animal models that use shock tubes are extensively used in laboratories to simulate field conditions, to identify mechanisms of injury, and to develop injury thresholds. In this article, we place rats in different locations along the length of the shock tube (i.e., inside, outside, and near the exit), to examine the role of animal placement location (APL) in the biomechanical load experienced by the animal. We found that the biomechanical load on the brain and internal organs in the thoracic cavity (lungs and heart) varied significantly depending on the APL. When the specimen is positioned outside, organs in the thoracic cavity experience a higher pressure for a longer duration, in contrast to APL inside the shock tube. This in turn will possibly alter the injury type, severity, and lethality. We found that the optimal APL is where the Friedlander waveform is first formed inside the shock tube. Once the optimal APL was determined, the effect of the incident blast intensity on the surface and intracranial pressure was measured and analyzed. Noticeably, surface and intracranial pressure increases linearly with the incident peak overpressures, though surface pressures are significantly higher than the other two. Further, we developed and validated an anatomically accurate finite element model of the rat head. With this model, we determined that the main pathway of pressure transmission to the brain was through the skull and not through the snout; however, the snout plays a secondary role in diffracting the incoming blast wave towards the skull. ; Peer reviewed

Traumatic brain injury (TBI), particularly explosive blast-induced TBI (bTBI), has become the most prevalent injury among military personnel. The disruption of cognitive function is one of the most serious consequences of bTBI because its long-lasting effects prevent survivors fulfilling their active duty and resuming normal civilian life. However, the mechanisms are poorly understood and there is no treatment available. This study investigated the effects of adenosine A2A receptor (A2AR) on bTBI-induced cognitive deficit, and explored the underlying mechanisms. After being subjected to moderate whole-body blast injury, mice lacking the A2AR (A2AR knockout (KO)) showed less severity and shorter duration of impaired spatial reference memory and working memory than wild-type mice did. In addition, bTBI-induced cortical and hippocampal lesions, as well as proinflammatory cytokine expression, glutamate release, edema, cell loss, and gliosis in both early and prolonged phases of the injury, were significantly attenuated in A2AR KO mice. The results suggest that early injury and chronic neuropathological damages are important mechanisms of bTBI-induced cognitive impairment, and that the impairment can be attenuated by preventing A2AR activation. These findings suggest that A2AR antagonism is a potential therapeutic strategy for mild-to-moderate bTBI and consequent cognitive impairment.

Chronic low-level blast exposure has been linked with neurological alterations and traumatic brain injury (TBI) biomarkers. Impaired smooth-pursuit eye movements (SPEM) are often associated with TBI. The purpose of this study was to determine whether long-term operators of low-level blast exposure or high-caliber weapons use displayed oculomotor behaviors that differed from controls. Twenty-six members of an elite military unit performed a computerized oculomotor testing task using an eye tracker and completed a concussion assessment questionnaire. The participants were split into a blast exposure group and control group. The blast exposure group had a history of exposure to low-level blasts or high-caliber weapon use. The results revealed significant differences in SPEM, saccades, and fixations between the blast exposure group and control group. The blast exposure group's eye movements were slower, stopped at more frequent points when following a target, traveled further from the target in terms of both speed and direction, and showed higher rates of variation and inefficiency. Poor oculomotor behavior correlated with a higher symptom severity on the concussion assessment questionnaire. Military special operators exposed to long-term low-level blasts or high-caliber weapons usage displayed an impaired oculomotor behavior in comparison to controls. These findings further our understanding of the impact of long-term low-level blast exposure on the oculomotor behavior of military special operators and may inform practical implications for military training.

Chronic low-level blast exposure has been linked with neurological alterations and traumatic brain injury (TBI) biomarkers. Impaired smooth-pursuit eye movements (SPEM) are often associated with TBI. The purpose of this study was to determine whether long-term operators of low-level blast exposure or high-caliber weapons use displayed oculomotor behaviors that differed from controls. Twenty-six members of an elite military unit performed a computerized oculomotor testing task using an eye tracker and completed a concussion assessment questionnaire. The participants were split into a blast exposure group and control group. The blast exposure group had a history of exposure to low-level blasts or high-caliber weapon use. The results revealed significant differences in SPEM, saccades, and fixations between the blast exposure group and control group. The blast exposure group's eye movements were slower, stopped at more frequent points when following a target, traveled further from the target in terms of both speed and direction, and showed higher rates of variation and inefficiency. Poor oculomotor behavior correlated with a higher symptom severity on the concussion assessment questionnaire. Military special operators exposed to long-term low-level blasts or high-caliber weapons usage displayed an impaired oculomotor behavior in comparison to controls. These findings further our understanding of the impact of long-term low-level blast exposure on the oculomotor behavior of military special operators and may inform practical implications for military training.

Most traumatic brain injuries (TBIs) during military deployment or training are clinically "mild" and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, ...

There is an increasing incidence of military traumatic brain injury (TBI), and similar injuries are seen in civilians in war zones or terrorist incidents. Indeed, blast-induced mild TBI has been referred to as the signature injury of the conflicts in Iraq and Afghanistan. Assessment involves schemes that are common in civilcian practice but, in common with civilian TBI, takes little account of information available from modern imaging (particularly diffusion tensor magnetic resonance imaging) and emerging biomarkers. The efficient logistics of clinical care delivery in the field may have a role in optimizing outcome. Clinical care has much in common with civilian TBI, but intracranial pressure monitoring is not always available, and protocols need to be modified to take account of this. In addition, severe early oedema has led to increasing use of decompressive craniectomy, and blast TBI may be associated with a higher incidence of vasospasm and pseudoaneurysm formation. Visual and/or auditory deficits are common, and there is a significant risk of post-traumatic epilepsy. TBI is rarely an isolated finding in this setting, and persistent post-concussive symptoms are commonly associated with post-traumatic stress disorder and chronic pain, a constellation of findings that has been called the polytrauma clinical triad.

Blast-induced mild traumatic brain injury (mTBI) is of particular concern among military personnel due to exposure to blast energy during military training and combat. The impact of primary low-intensity blast mediated pathophysiology upon later neurobehavioral disorders has been controversial. Developing a military preclinical blast model to simulate the pathophysiology of human blast injury is an important first step. This article provides an overview of primary blast effects and perspectives of our recent studies demonstrating ultrastructural changes in the brain and behavioral disorders resulting from open-field blast exposures up to 46.6 kPa using a murine model. The model is scalable and permits exposure to varying magnitudes of primary blast injuries by placing animals at different distances from the blast center or by changing the amount of C4 charge. We here review the implications and future applications and directions of using this animal model to uncover the underlying mechanisms related to primary blast injury. Overall, these studies offer the prospect of enhanced understanding of the pathogenesis of primary low-intensity blast-induced TBI and insights for prevention, diagnosis and treatment of blast induced TBI, particularly mTBI/concussion related to current combat exposures.

Fundamental questions remain unanswered about the longitudinal impact of blast-plus-impact complex traumatic brain injuries (TBI) from wars in Iraq and Afghanistan. This prospective, observational study investigated measures of clinical outcome in US military personnel evacuated to Landstuhl Regional Medical Center (LRMC) in Germany after such "blast-plus" concussive TBIs. Glasgow Outcome Scale-Extended assessments completed 6–12 months after injury indicated a moderate overall disability in 41/47 (87%) blast-plus TBI subjects and a substantial but smaller number (11/18, 61%, p=0.018) of demographically similar US military controls without TBI evacuated for other medical reasons. Cognitive function assessed with a neuropsychological test battery was not different between blast-plus TBI subjects and controls; performance of both groups was generally in the normal range. No subject was found to have focal neurological deficits. However, 29/47 (57%) of blast-plus subjects with TBI met all criteria for post-traumatic stress disorder (PTSD) versus 5/18 (28%) of controls (p=0.014). PTSD was highly associated with overall disability; 31/34 patients with PTSD versus 19/31 patients who did not meet full PTSD criteria had moderate to severe disability (p=0.0003). Symptoms of depression were also more severe in the TBI group (p=0.05), and highly correlated with PTSD severity (r=0.86, p<0.0001). Thus, in summary, high rates of PTSD and depression but not cognitive impairment or focal neurological deficits were observed 6–12 months after concussive blast-plus-impact complex TBI. Overall disability was substantially greater than typically reported in civilian non-blast concussive ("mild") patients with TBI, even with polytrauma. The relationship between these clinical outcomes and specific blast-related aspects of brain injuries versus other combat-related factors remains unknown.

Military personnel involved in Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) commonly experience blast-induced mild to moderate traumatic brain injury (TBI). In this study, we used task-activated functional MRI (fMRI) to determine if blast-related TBI has a differential impact on brain activation in comparison with TBI caused primarily by mechanical forces in civilian settings. Four groups participated: (1) blast-related military TBI (milTBI; n=21); (2) military controls (milCON; n=22); (3) non-blast civilian TBI (civTBI; n=21); and (4) civilian controls (civCON; n=23) with orthopedic injuries. Mild to moderate TBI (MTBI) occurred 1 to 6 years before enrollment. Participants completed the Stop Signal Task (SST), a measure of inhibitory control, while undergoing fMRI. Brain activation was evaluated with 2 (mil, civ)×2 (TBI, CON) analyses of variance, corrected for multiple comparisons. During correct inhibitions, fMRI activation was lower in the TBI than CON subjects in regions commonly associated with inhibitory control and the default mode network. In contrast, inhibitory failures showed significant interaction effects in the bilateral inferior temporal, left superior temporal, caudate, and cerebellar regions. Specifically, the milTBI group demonstrated more activation than the milCON group when failing to inhibit; in contrast, the civTBI group exhibited less activation than the civCON group. Covariance analyses controlling for the effects of education and self-reported psychological symptoms did not alter the brain activation findings. These results indicate that the chronic effects of TBI are associated with abnormal brain activation during successful response inhibition. During failed inhibition, the pattern of activation distinguished military from civilian TBI, suggesting that blast-related TBI has a unique effect on brain function that can be distinguished from TBI resulting from mechanical forces associated with sports or motor vehicle accidents. The implications of these findings for diagnosis ...

The increased incidence of improvised explosives in military conflicts has brought about an increase in the number of traumatic brain injuries (TBIs) observed. Although physical injuries are caused by shrapnel and the immediate blast, encountering the blast wave associated with improvised explosive devices (IEDs) may be the cause of traumatic brain injuries experienced by warfighters. Assessment of the effectiveness of personal protective equipment (PPE) to mitigate TBI requires understanding the interaction between blast waves and human bodies and the ability to replicate the pressure signatures caused by blast waves. Prior research has validated compression-driven shock tube designs as a laboratory method of generating representative pressure signatures, or Friedlander-shaped blast profiles; however, shock tubes can vary depending on their design parameters and not all shock tube designs generate acceptable pressure signatures. This paper presents a comprehensive numerical study of the effects of driver gas, driver (breech) length, and membrane burst pressure of a constant-area shock tube. Discrete locations in the shock tube were probed, and the blast wave evolution in time at these points was analyzed to determine the effect of location on the pressure signature. The results of these simulations are used as a basis for suggesting guidelines for obtaining desired blast profiles.

Blast-related traumatic brain injury (bTBI) poses a significant concern for military personnel engaged in Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF). Given the highly stressful context in which such injury occurs, psychiatric comorbidities are common. This paper provides an overview of mild bTBI and discusses the cognitive sequelae and course of recovery typical of mild TBI (mTBI). Complicating factors that arise in the context of co-morbid posttraumatic stress disorder (PTSD) are considered with regard to diagnosis and treatment. Relatively few studies have evaluated the efficacy of cognitive rehabilitation in civilian mTBI, but we discuss cognitive training approaches that hold promise for addressing mild impairments in executive function and memory, akin to those seen in OEF/OIF veterans with bTBI and PTSD. Further research is needed to address the patient and environmental characteristics associated with optimal treatment outcome.

BACKGROUND: Traumatic brain injury (TBI) is a well-known brain dysfunction commonly encountered in activities such as military combat or collision sports. The etiopathology can vary depending on the context and bomb explosions are becoming increasingly common in war zones, urban terrorist attacks, and civilian criminal feuds. Blast-related TBI may cause the full severity range of neurotrauma, from a mild concussion to severe, penetrating injury. Recent classifications of the pathophysiological mechanisms comprise five factors that reflect the gravity of the experienced trauma and suggest to the clinician different pathways of injury and consequent pathology caused by the explosion. CASE DESCRIPTION: In the present report, the authors describe a case of 26 years old presenting with blast-related severe TBI caused by the detonation of an explosive in an amusement arcade. Surgical decompression to control intracranial pressure and systemic antibiotic treatment to manage and prevent wound infections were the main options available in a civilian hospital. CONCLUSION: While numerous studies examined the burden of blast-related brain injuries on service members, few papers have tackled this problem in a civilian setting, where hospitals are not sufficiently equipped, and physicians lack the necessary training. The present case demonstrates the urgent need for evidence-based diagnostic and therapeutic protocols in civilian hospitals that would improve the outcome of such patients.

Exposure to explosive shockwave often leads to blast-induced traumatic brain injury in military and civilian populations. Unprotected ears are most often damaged following exposure to blasts. Although there is an association between tympanic membrane perforation and TBI in blast exposure victims, little is known about how and to what extent blast energy is transmitted to the central nervous system via the external ear canal. The present study investigated whether exposure to blasts directed through the ear canal causes brain injury in Long-Evans rats. Animals were exposed to a single blast (0–30 pounds per square inch (psi)) through the ear canal, and brain injury was evaluated by histological and behavioral outcomes at multiple time-points. Blast exposure not only caused tympanic membrane perforation but also produced substantial neuropathological changes in the brain, including increased expression of c-Fos, induction of a profound chronic neuroinflammatory response, and apoptosis of neurons. The blast-induced injury was not limited only to the brainstem most proximal to the source of the blast, but also affected the forebrain including the hippocampus, amygdala and the habenula, which are all involved in cognitive functions. Indeed, the animals exhibited long-term neurological deficits, including signs of anxiety in open field tests 2 months following blast exposure, and impaired learning and memory in an 8-arm maze 12 months following blast exposure. These results suggest that the unprotected ear canal provides a locus for blast waves to cause TBI. This study was approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center (Animal protocol# 0932E, approval date: September 30, 2016 and 0932F, approval date: September 27, 2019).